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Ribosomal Synthesis of Diketone-containing Peptide Backbone via Post-Translational Acyl Shift

Talk given by Carly Schissel (UC Berkeley) as part of the International GCE Webinar series. Live talk given on October 17th, 2024. Despite tremendous efforts to engineer translational machinery, replacing the encoded peptide backbone with new-to-Nature structures remains a significant and largely unmet challenge. We discovered that peptides containing a dehydrolactic acid motif rapidly isomerize to generate a backbone-embedded α,γ-diketoamide via a spontaneous formal O to C acyl shift. The dehydrolactic acid motif can be introduced into peptides ribosomally or via solid-phase synthesis using α-hydroxy phenylselenocysteine followed by oxidation. Subsequent incubation at physiological pH produces an α,γ-diketoamide that can be diversified using a variety of nucleophiles, including hydrazines and hydroxylamines to form pyrazoles and oximes, respectively. This general strategy, predicated on an intricate cascade of acyl rearrangements, provides the first example of a C–C bond forming reaction to take place within the peptide backbone, as well as the first ribosomal strategy for generating protein-like materials with diverse, backbone-embedded heterocycles.